1. Field of the Invention
This present invention generally relates to compounds of Theophylline and 3-Isobutyl-1-methylxanthine (IBMX) having N-7 substituted derivatives, and more particularly to the compounds and use of such compounds in various pharmacological applications.
2. Background Information
The endothelium plays a major role in regulating vascular smooth muscle (VSM) tone through the release of a variety of vasoactive factors. Among the endothelium-derived vasodilators, nitric-oxide (NO) is probably the primary mediator of endothelium-dependent relaxation in most blood vessels. Nitric Oxide in numerous bioregulatory pathways has not only expanded new therapeutic related compounds but has also led to an increased use of such compounds in pharmacological studies.
In recent years, the nitric oxide gas has been shown to be an important regulator of vascular functions by controlling blood vessel tone as well as blood cell interactions with the vascular wall. (S. Moncada et al., Pharmacol. Rev. vol. 43, No. 2, pp. 109-142, 1991). The action of NO (Nitric Oxide) as a vasodilator is mediated by the activation of vascular smooth muscle soluble guanylyn cyclase (sCG), a signal tranduction enzyme which forms the second messenger of molecular cyclic GMP (William P. Arnold et al., Proc. Natl Acad Sci. vol. 74 No. 8 pp. 3203-3207, 1977 Charles J. Lowenstein et al. Ann. Intern. Med. Vol 102, No. 3 pp. 227-237, 1994). The activity of several cyclic GMP (guanosine 3′5′-cyclic monophosphate) which lead to vasorelaxation has been determined. The membrane-bound guanylyl cyclases are receptor-like enzymes which are activated by extracellular binding of natriuretic peptides. In contrast, soluble guanylyl cyclases act via their hemoglobin group which is an important intracellular receptor for nitric oxide. (Paulus Wohlfart et al Br. J. Pharmcol. Vol. 128, pp. 1316-1322, 1999) Moreover, the increases in cGMP with these guanylyl cyclase activators and phosphodiesterases (PDE) or cGMP breakdown inhibition which have been associated with the relaxation of vascular and tracheal smooth muscles.
These interactions between endogenous NO or NO donors and endothelium-derived hyperpolarizing factor (EDHF) or K+ channels have received a great deal of attention. (Fransisco Perez Viscaino, et al. Brisitsh J. Pharmacol. Vol. 123, pp. 847-854, 1998). K+ channels play a major role in the regulation of the resting membrane potential and modulate VSM (vascular smooth muscle) tone. (Mark T. Nelson & John M. Quayle, Am. J. Physiol. vol 268, C799-C822, 1995). The endothelium-derived hyperpolarizing factor activates the potassium channels, and the potassium flux hyperpolarizes and thus relaxes the smooth muscle cell. Recent findings suggest that activation of endothelium KATP channels (ATP-sensitive potassium channels) may also release endothelium-derived nitric oxide (Ethel C. Feleder & Edda Adler-Graschinsky Eur. J. pharmacol. Vol. 319 pp. 229-238, 1997) or endothelium-derived hyperpolarizing factor (Richard White and C. Robin Hiley, Eur. J. Pharmacol. Vol. 339, p157-160 1997). Nitric oxide donors have been shown to activate KATP channels via a cyclic GMP-dependent mechanism, presumably involving activation of cyclic GMP-dependent protein kinase in rat aortic smooth muscle cells (Masahiro Kubo et al., Circ. Res. Vol. 74 No. 3 pp. 471-476, 1993) and rabbit mesenteric artery (Michael E. Murphy & Joseph E. Brayden, J. Physiol. Vol. 486, No. 1 pp. 47-48, 1995) and by a cyclic GMP-independent mechanism in the rat mesenteric artery. (Thomas Weidelt et al., J. Physiol. Vol. 500, No. 3 pp. 617-630, 1997) Although most of the endothelium-dependent relaxation is due to NO (nitric oxide), hyperpolarization associated with the K+ channels opening can supplement 60-80% of this response if no synthesis is blocked. (E. V. Kilpatrick & T. M. Cocks Br. J. Pharmacol. vol. 112 pp. 557-565, 1994)
The combination activity of soluble guanylyl cyclase (sGC) stimulation and K+ channels opening in a molecule such as that found in nicorandil, although shown without phosphodiesterase (PDE) inhibition activity, is able to relax agonist-induced vasoconstriction more fully. (F. Perez-Vizcaino et al. Br, J. Pharmacol. vol. 123, pp. 847-854, 1998) YC-1(3-(5′-hydroxymethyl-2-furyl)-1-benzyl-indazole) is representative of a class of sGC activator with PDE (phosphodiesterase) inhibition and leads to a long-lasting cyclic GMP-mediated inhibition of vasoconstriction (Jan Gaile et al., Br. J. Pharmacol. vol 127, pp 195-203, 1999).
The present invention includes various theophylline and 3-isobutyl-1-methylxanthine (IBMX) compounds having N-7 derivatives. In laboratory testing on animals, these compounds have been shown to possess desired inhibitory activities on PDE-5 Phosphodiesterase.
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows and in part will become apparent to those skilled in the art upon examination of the following or may be learned by practice of the invention. The objects and advantages of the invention may be realized and attained by means of the instrumentalities and combinations particularly pointed out in the appended claims.